Post-Ischemic Cardioprotection by A2A Adenosine Receptors: Dependent of Phosphatidylinositol 3-Kinase Pathway

Boucher, Matthieu; Pesant, Stéphanie; Falcao, Stéphanie; Montigny, Chantal de; Schampaert, Erick; Cardinal, René; Rousseau, Guy

doi:10.1097/00005344-200403000-00013

Cited by 49 publications

(46 citation statements)

References 29 publications

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“…It was surprising that the antihypertrophic effects of adenosine receptor agonists were similarly observed with agents acting on the A 1 , A 2A , and A 3 receptors in relatively equal fashion. Nonetheless, despite the fact that these receptors are coupled to diverse cell signaling processes, activators of multiple adenosine receptor subtypes have also been shown to protect the ischemic and reperfused myocardium (Yao and Gross, 1993;Auchampach et al, 2003;Boucher et al, 2004). In the present study, the antihypertrophic effect of adenosine agonists was associated with prevention of early up-regulation of the immediate early gene c-fos which is likely an important event during the development of early hypertrophy (Babu et al, 2000).…”

Section: Discussionmentioning

confidence: 52%

Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Gan¹,

Rajapurohitam²,

Haist³

et al. 2004

J Pharmacol Exp Ther

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Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 M) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A 1 receptor agonist N 6 -cyclopentyladenosine (1 M), the A 2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5Ј-N-ethylcarboxamidoadenosine (100 nM), and the A 3 receptor agonist N 6 -(3-iodobenzyl)adenosine-5Ј-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.

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Section: Discussionmentioning

confidence: 52%

Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Gan¹,

Rajapurohitam²,

Haist³

et al. 2004

J Pharmacol Exp Ther

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“…We have measured the activity of the caspase-3 and -8 after 15 minutes of reperfusion because previous data indicate that this activity is high during the first minute of reperfusion to reduce, and it is also basal at 5 hours of reperfusion [23].…”

Section: Discussionmentioning

confidence: 99%

Dual effect of pre-ischemic administration of TNF-alpha on myocardial infarct size

Quang¹,

Hatem²,

Rousseau³

et al. 2013

WJCD

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Tumour necrosis factor-α is a cytokine released during myocardial infarction. According to the literature, the effect of TNFα on myocardial infarction is controversial, especially when administered before the ischemic period. The deleterious effects of TNFα seem to be related to the triggering of apoptosis. This study has been designed to determine if different doses of TNFα, administered before the ischemic period, have the same effect on infarct size and on activation of caspase-3 and -8, two enzymes involved in apoptosis. Four groups, using a porcine model of myocardial infarction, have been used: placebo and TNFα (0.1 µg/kg; 1 µg/kg and 3 µg/kg). All administered 15 minutes before a 50 minutes occlusion of the left anterior descending artery. Myocardial infarct size has been determined at 3 hours of reperfusion. In a subgroup of animals, reperfusion period has been limited to 15 min to determine the activity of caspase-3 and -8 by spectrofluorometry. Results indicated that infarct size is significantly smaller in groups 0.1 µg/kg and 1 µg/ kg as compared to the placebo group. In contrast, the 3 µg/kg group presented an infarct size similar to the placebo group. Activity of caspase-3 and -8 is reduced in the ischemic region in groups 0.1 and 1 µg/ kg as compared to the placebo group whereas activity in the 3 µg/kg group was similar to the placebo. The results obtained indicated that a low dose of TNFα administered before the ischemic period reduces infarct size, whereas the cardioprotection is lost with the high dose.

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“…In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10]. Inflammatory modulation contributes to this latter cardioprotection [9][10][11], together with the regulation of myocyte kinase signals to limit oxidative stress, mitochondrial dysfunction and cell death [12][13][14]. However, impacts of the A 2A R on integrated myocardial responses to uncontrolled inflammation, and the mechanisms underlying such effects, remain to be elucidated.…”

Section: J Ashton and Melissa E Reichelt Denotes Equal First Authormentioning

confidence: 99%

“…Receptor deletion fails to modify inflammatory markers/injury in some studies [22], reportedly worsens endotoxemic injury in heart [23] and lung [15,24] and improves survival in models of polymicrobial sepsis [25,26]. These divergent outcomes may reflect different cell-and organ-specific effects of A 2A Rs, for example promoting inflammasome formation and macrophage-dependent injury [27], impairing bacterial clearance [25], while activating cardiac survival signalling and suppressing inflammation [3,7,[12][13][14]. Nonetheless, opposing effects of endogenous vs. exogenous (or amplified endogenous) adenosine are evident within cell types, for example inhibiting vs. promoting vascular myocyte NOS activation with inflammation [28].…”

Section: J Ashton and Melissa E Reichelt Denotes Equal First Authormentioning

confidence: 99%

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

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Influences of adenosine 2A receptor (A 2A R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A 2A R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A 2A R-sensitive genes modified by A 2A R KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of tolllike receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca 2+ signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by A 2A R KO, supporting inflammatory suppression via A 2A R sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A 2A Rs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STATsignalling and cardiac injury without influencing cardiac depression in endotoxemia.

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Post-Ischemic Cardioprotection by A2A Adenosine Receptors: Dependent of Phosphatidylinositol 3-Kinase Pathway

Cited by 49 publications

References 29 publications

Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Dual effect of pre-ischemic administration of TNF-alpha on myocardial infarct size

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

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